Tau, a major microtubule-associated protein (MAP), has been implicated in Alzheimer's disease (AD) and a variety of other neurological conditions collectively referred to as tauopathies. Remarkably, the functions tau fulfills in the adult brain and the exact roles it plays in the pathogenesis of these conditions remain uncertain. The current application aims to address these flagrant knowledge gaps by generating novel mouse models in which the expression of tau can be suppressed in specific brain regions and neural cell types in adult mice. Another important factor involved in AD is the amyloid- (A) peptide, which is derived from the amyloid precursor protein (APP). Crossing human APP (hAPP) transgenic (TG) mice with high levels of A in the brain onto a complete (Tau-/-) or partial (Tau+/-) tau-deficient background prevented most of their A-dependent abnormalities, including impairments in learning and memory, abnormal neural network activity, and various related biochemical and anatomical neuronal alterations. Tau reduction achieved this striking rescue without changing A levels or deposition in the brain. Furthermore, our hAPP/Tau+/+ mice never develop neurofibrillary tangles, and their wildtype murine tau is expressed at physiological levels, has normal solubility, and shows no evidence for the type of abnormal phosphorylation or aggregation seen in AD and mutant-tau TG models. Tau reduction is the most effective strategy to prevent A-induced neuronal deficits we have identified so far, but the safety of this approach in adult animals and the underlying mechanisms remain unknown. Our preliminary studies also revealed that tau reduction makes mice without hAPP/A expression more resistant against chemically induced seizures, suggesting a novel role for tau in the regulation of neuronal/synaptic activity. However, why and how tau reduction increases resistance to epileptic seizures is unknown. The above constellation of preliminary findings and unresolved questions underlines the significance and novelty of the experiments described in the current application. We currently have no effective ways to treat or prevent AD. If tau reduction was as efficacious and safe in preventing cognitive dysfunction in humans with AD as it is in hAPP mice, further exploration of this strategy might lead to a therapeutic breakthrough. In addition, tau reduction might be of benefit in other neurological disorders in which excitotoxicity plays a role. To address these challenges and opportunities, we propose the following specific aims. Aim 1. Decrease tau levels in brains of adult hAPP mice and NTG controls with viral vectors expressing anti-tau shRNA. Aim 2. Generate transgenic mice with regulatable expression of anti-tau shRNA. Aim 3. Analyze the models generated in Aims 1 and 2 behaviorally, anatomically and biochemically. Generation of the proposed mouse models should allow us to directly address the following questions to which there currently are no clear answers: Is tau reduction efficacious and safe when implemented in adulthood? In which brain region and neuronal cell types (e.g., neuronal vs. glial, excitatory vs. inhibitory neurons) does tau have to be reduced in order to prevent A- dependent cognitive decline and to increase resistance against chemically induced seizures? In the long run, the proposed models could help decipher the function(s) of tau in the adult brain, its role in disease-related neuronal dysfunction, and the underlying molecular mechanisms. PUBLIC HEALTH RELEVANCE: Amyloid- (A) is widely thought to cause Alzheimer's disease (AD). We recently discovered that reducing the protein Tau can prevent A from causing memory deficits and related neuronal impairments in AD mouse models. In this proposal, we will assess the efficacy and safety of this novel therapeutic strategy at the preclinical level.